Abstract
Small molecules found in natural products provide therapeutic benefits due to their pharmacological or biological activity, which may increase or decrease the expression of human epidermal growth factor receptor (HER), a promising target in the modification of signaling cascades involved in excessive cellular growth. In this study, in silico molecular protein-ligand docking protocols were performed with AutoDock Vina in order to evaluate the interaction of 800 natural compounds (NPs) from the NatProd Collection (http://www.msdiscovery.com/natprod.html), with four human HER family members: HER1 (PDB: 2ITW), HER2 (PDB: 3PP0), HER3 (PDB: 3LMG) and HER4 (PDB: 2R4B). The best binding affinity values (kcal/mol) for docking pairs were obtained for HER1-podototarin (−10.7), HER2-hecogenin acetate (−11.2), HER3-hesperidin (−11.5) and HER4-theaflavin (−10.7). The reliability of the theoretical calculations was evaluated employing published data on HER inhibition correlated with in silico binding calculations. IC50 values followed a significant linear relationship with the theoretical binding Affinity data for HER1 (R = 0.656, p < 0.0001) and HER2 (R = 0.543, p < 0.0001), but not for HER4 (R = 0.364, p > 0.05). In short, this methodology allowed the identification of several NPs as HER inhibitors, being useful in the discovery and design of more potent and selective anticancer drugs.
Highlights
The epidermal growth factor receptor, EGFR, is a transmembrane receptor tyrosine kinase (RTK), known to be overexpressed in approximately 90% of tumors [1] that strongly affects the quality of life and outcomes of cancer patients all over the world [2]
It is currently affiliated to the ErbB/human epidermal growth factor receptor (HER) family of receptors which comprises of four structurally related signaling oncoproteins HER1 (EGFR/ErbB1), HER2 (ErbB2/Neu), HER3 (ErbB3), and HER4 (ErbB4) [3]
The activation of HER receptors is the result of their ability to bind effectively to different ligands, like epidermal growth factor (EGF), transforming growth factor-α (TGFA), heparin-binding EGF-like growth factor, amphiregulin, betacellulin, epiregulin and the latest addition to the mammalian family of EGFR, epigen [16], either or to one or more receptors
Summary
The epidermal growth factor receptor, EGFR, is a transmembrane receptor tyrosine kinase (RTK), known to be overexpressed in approximately 90% of tumors [1] that strongly affects the quality of life and outcomes of cancer patients all over the world [2]. The receptor is composed of different elements, such as a glycosylated extracellular domain, a single hydrophobic transmembrane segment, an intracellular portion with a regulatory juxtamembrane segment, a carboxy terminal tail composed of specific tyrosine-containing sequences and a key protein kinase domain [4,5] These receptors play a major role in the modulation of diverse cellular functions, such as cell proliferation, differentiation, adhesion, survival, motility [3] and programmed cell death [6] that are often dysregulated, generating a cascade of responses able to promote the formation and progression of various malignancies such as: glioblastoma [7], muscle invasive bladder cancer [8], non-small-cell lung cancer [9], squamous cell carcinoma of the skin [10], gastric cancer [11] and breast cancer [12], via aberrant overexpression, kinase activation and mutation. After ligand binding to the extracellular domain of the receptor, a conformational change takes place in form of functionally active dimers (EGFR-EGFR (homodimer) or EGFR-HER2, EGFR-HER3, EGFR-HER4 (heterodimer))
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